- Open Access
Data mining of the transcriptome of Plasmodium falciparum: the pentose phosphate pathway and ancillary processes
© Bozdech and Ginsburg; licensee BioMed Central Ltd. 2005
- Received: 15 January 2005
- Accepted: 18 March 2005
- Published: 18 March 2005
The general paradigm that emerges from the analysis of the transcriptome of the malaria parasite Plasmodium falciparum is that the expression clusters of genes that code for enzymes engaged in the same cellular function is coordinated. Here the consistency of this perception is examined by analysing specific pathways that metabolically-linked. The pentose phosphate pathway (PPP) is a fundamental element of cell biochemistry since it is the major pathway for the recycling of NADP+ to NADPH and for the production of ribose-5-phosphate that is needed for the synthesis of nucleotides. The function of PPP depends on the synthesis of NADP+ and thiamine pyrophosphate, a co-enzyme of the PPP enzyme transketolase. In this essay, the transcription of gene coding for enzymes involved in the PPP, thiamine and NAD(P)+ syntheses are analysed. The genes coding for two essential enzymes in these pathways, transaldolase and NAD+ kinase could not be found in the genome of P. falciparum. It is found that the transcription of the genes of each pathway is not always coordinated and there is usually a gene whose transcription sets the latest time for the full deployment of the pathway's activity. The activity of PPP seems to involve only the oxidative arm of PPP that is geared for maximal NADP+ reduction and ribose-5-phosphate production during the early stages of parasite development. The synthesis of thiamine diphosphate is predicted to occur much later than the expression of transketolase. Later in the parasite cycle, the non-oxidative arm of PPP that can use fructose-6-phosphate and glyceraldehyde-3-phosphate supplied by glycolysis, becomes fully deployed allowing to maximize the production of ribose-5-phosphate. These discrepancies require direct biochemical investigations to test the activities of the various enzymes in the developing parasite. Notably, several transcripts of PPP enzyme-coding genes display biphasic pattern of transcription unlike most transcripts that peak only once during the parasite cycle. The physiological meaning of this pattern requires further investigation.
- Pentose Phosphate Pathway
- Thiamine Deficiency
- Parasite Development
- Thiamine Pyrophosphate
The analysis of the transcriptome of Plasmodium falciparum has revealed that during the intraerythrocytic development of the parasite, genes coding for enzymes and proteins that are involved in complex cellular functions such as transcription, replication or energy metabolism, each involving many gene products, are transcribed in a coordinated fashion, supporting the notion that all components must be present at the right time to allow for optimal function [1–3]. While this may be true in general, it has already been found that scrutinizing the details of specific metabolic functions reveal some significant departures from this paradigm . Such scrutiny has also provided some intriguing peculiarities that through detailed biochemical studies may reveal some parasite-specific functions that may enlighten our understanding of parasitism or even provide for novel targets for chemotherapeutic intervention. The present analysis explores of the transcriptome to fathom additional metabolic pathways.
The reactions of the PPP operate exclusively in the cytoplasm. PPP has both an oxidative and a non-oxidative arm. The oxidation steps, utilizing glucose-6-phosphate (G6P) as the substrate, occur at the beginning of the pathway and are the reactions that generate NADPH. Thus, the first carbon of glucose-6-phosphate is first oxidized to a lactone (catalyzed by glucose-6-phosphate dehydrogenase) concomitantly releasing two electrons that reduce one molecule of NADP+ to NADPH. The ensuing decarboxylation of 6-phospho-D-gluconate (catalyzed by 6-phosphogluconate dehydrogenase) releases two additional electrons, which reduce a second molecule of NADP+. A five-carbon sugar, D-ribulose-5-phosphate, is produced in the reaction. By isomerization, D-ribulose-5-phosphate is transformed into D-ribose-5-phosphate (R5P). To be used in nucleic acid synthesis, R5P is transformed into 5-Phospho-?-D-ribose 1-pyrophosphoric acid (PRPP) by ribose-phosphate diphosphokinase (EC: 18.104.22.168).
The non-oxidative reactions of the PPP are primarily designed to generate R5P. Equally important reactions of the PPP are to convert dietary 5 carbon sugars or D-ribose-1-phosphate generated in the salvage of purines (that can be slowly converted to R5P by phosphoglucomutase; EC: 22.214.171.124) into both 6 (fructose-6-phosphate) and 3 (glyceraldehyde-3-phosphate) carbon sugars which can then be utilized by the pathways of glycolysis. In the first reaction, R5P will accept two carbon atoms from xylulose-5-phosphate (obtained by epimerization of ribulose-5-P), yielding sedoheptulose-7-phosphate and glyceraldehyde-3-phosphate (catalyzed by transketolase). Sedoheptulose-7-phosphate transfers three carbons to glyceraldehyde-3-phosphate (catalyzed by transaldolase), yielding fructose-6-phosphate (F6P) and erythrose-4-phosphate. Erythrose-4-phosphate then accepts two carbon atoms from a second molecule of xylulose-5-phosphate (catalyzed again by transketolase), yielding a second molecule of F6P and a glyceraldehyde-3-P (GAP) molecule. F6P and a GAP can then enter glycolysis and eventually produce ATP. The intermediate erythrose-4-phosphate is a substrate for the shikimate pathway http://sites.huji.ac.il/malaria/maps/shikimatebiopath.html.
The genes that code for enzymes participating in ancillary processes that produce NADP+ and thiamine pyrophosphate, that serves as a co-factor for transketolase activity, should be expressed in coordination with the enzymes of the PPP. The details of the mentioned pathways can be also grasped at (http://sites.huji.ac.il/malaria/maps/nicotinatemetpath.html; http://sites.huji.ac.il/malaria/maps/thiaminemetpath.html, respectively) and the time-dependent transcription of the genes coding for the different enzymes will be discussed below.
PPP activity in P. falciparum- infected erythrocytes has been measured [5–7]. The reverse activity of the non-oxidative arm of PPP has also been demonstrated by measuring the incorporation of radiolabel from [1-14C]glucose into nucleotides [6, 8]. The former investigators have shown that 4/5 of the glucose incorporated into parasite nucleic acids comes from the condensation of F6P and GAP in the reverse action of this arm. Atamna et al, reported that infected cells have large increase of PPP activity where 82 % is contributed by the parasite while the host cell's PPP activity is activated some 24-fold as a result of the oxidative stress that the parasite generates and impinges on the host cell .
The gene coding for G6PD has been cloned  and the biochemical properties of the isolated enzyme have been characterized [11, 12]. Molecular investigations have revealed that G6PD is coded by a hybrid gene that contains also the sequence of 6-phosphogluconolactonase (the second enzyme of PPP) [13, 14]. Activity of 6-phosphogluconate dehydrogenase in Plasmodium- infected erythrocytes has been detected indirectly and alluded to a parasite enzyme, but not characterized [15–17]. Ribose-phosphate diphosphokinase of P. falciparum activity has been characterized and levels of its product 5'-phosphoribosyl-pyrophospate (PRPP) were measured in P. falciparum- infectederythrocytes [8, 18]. The levels of PRPP were found to be increased 56-fold in infected cells at the trohozoite stage compared to uninfected erythrocytes.
NADP utilizing enzymes Enzymes are arranged by their sequential functional order. They are given by their name, their EC numbers, the gene identification (PfID) in the Plasmodium genome database (PlasmoDB), the time (in hours post invasion (HPI)) in the parasite's developmental cycle when they are maximally transcribed obtained from the IDC database and the metabolic function of the enzyme.
Fatty acid synthesis
Isocitrate dehydrogenase (NADP+);
Pyruvate dehydrogenase (acetyltransferring).
PF11 0256 PF14 0441
Glutamate dehydrogenase (NADP)
PF14 0164 PF14 0286
NAD(P)+ transhydrogenase (B-specific);
NADPH hemoprotein reductase
PF08 0066 PFL1550w
In this in silico analysis, the stage-dependent transcription of genes that code for enzymes that are involved in the PPP activity of the parasite will be analyzed in a functional context.
Enzymes of the pentose phosphate pathway and pyridine nucleotide metabolism. Enzymes are grouped into pathways. They are given by their name, their EC numbers, the gene identification (PfID) in the Plasmodium genome database (PlasmoDB)), the time (in hours post invasion (HPI)) in the parasite's developmental cycle when they are maximally transcribed obtained from the IDC database and the metabolic function of the enzyme.
Pentose phosphate pathway
Ribulose 5-phosphate 3-epimerase
Ribose 5-phosphate isomerase
Ribose phosphate diphosphokinase
PF13 0143 PF13 0157
Deoxyribose phosphate aldolase
Pyridine nucleotide metabolism
Nicotinate-nucleotide adenylyl transferase
Pyridine nucleotide transhydrogenase
Hydroxymethylpyrimidine kinase/ Phosphomethylpyrimidine kinase
At the onset of the present analysis, it should be underscored that time-dependent transcription does not always overlaps translation. Hence, transcript levels cannot be directly extrapolated to levels of their translated product. Moreover, transient transcription does not divulge on the stability of the translated products. Indeed, a recent analysis has shown for several genes that while the transcript peaks at the trophozoite stage and declines thereafter, the translated protein continues to accumulate . Significant discrepancies between mRNA and protein abundance in P. falciparum were also reported by LeRoche et al. . This was shown to be due to a delay between the maximum detection of an mRNA transcript and that of its cognate protein. Surely, a protein cannot be produced if its cognate gene is not transcribed. Therefore, the present analysis can at best set a time for possible translation but not for its actual occurrence. Thus, while transcript levels are informative for the concerted action of metabolically related enzymes, post-transcriptional mechanisms for controlling protein levels and protein stability must also be considered.
In this analysis, the transcription of genes coding for enzymes that constitute the PPP will be discussed first followed by those that are involved in the synthesis of NAD(P)+ and of thiamine pyrophosphate.
The pentose phosphate pathway
The situation of the non-oxidative arm genes is different. The gene that codes for ribose phosphate isomerase (EC: 126.96.36.199) peaks at 21 HPI and this seems to restrict the expression of the non-oxidative arm, since transketolase (EC: 188.8.131.52) is transcribed maximally immediately following invasion. Most importantly, the gene that codes for transaldolase (EC: 184.108.40.206) could not be found in the genome of P. falciparum (or in any other Plasmodium species sequenced so far, or in any other Apicomplexans for that matter) thus precluding the completion of the analysis of the non-oxidative arm transcription. As mentioned above, biochemical evidence indicates that this arm is active in the parasite. If it is indeed fully activated when ribose phosphate isomerase is transcribed (and supported by the transcription of the genes that code for ribose-phosphate diphosphokinase that peak at 21 HPI), it would match the transcription of the deoxyribonucleotide synthesis-related genes that starts at 18 HPI and peaks at 30 HPI  as well as those related to NADP+ synthesis. When the synthesis of ribonucleotides and deoxyribonucleotides ebbs off towards the end of the intraerythrocytic life cycle of the parasite, the PPP probably functions according to mode 3 (Figure 2) providing both NADPH and ATP. A feature that emerges from this analysis is that the transcription of the genes that code for enzymes acting in the non-oxidative arm are coordinated as shown for other clusters of genes whose products are functionally related [1–3]. However, it remains to be seen if the cognate enzymes of these transcripts are similarly coordinated since significant discrepancies between mRNA and protein abundance has been recently reported .
NAD+-utilizing enzymes. Enzymes are arranged by their sequential functional order. They are given by their name, their EC numbers, the gene identification (PfID) in the Plasmodium genome database (PlasmoDB), the time (in hours post invasion (HPI)) in the parasite's developmental cycle when they are maximally transcribed obtained from the IDC database, the metabolic function of the enzyme.
Pyrroline carboxylate reductase
Methionine polyamine metabolism
Ferrodoxin reductase-like protein
Enoyl-acyl carrier reductase
Fatty acid synthesis
2-oxoglutarate dehydrogenase el component
Lipoamide dehydrogenase, putative
Pyruvate dehydrogenase El component, ?-subunit
Fatty acid synthesis
NADH-cytochrome b5 reductase
Malate dehydrogenase, putative
PF11 0157 PFL0780w
Glycolysis; Glycerol metabolism
Mannose and fructose metabolism
Inosine-5 '-monophosphate dehydrogenase
3-methyl-2-oxobutanoate dehydrogenase (lipoamide)
Leucine, isoleucine and valine degradation
Inspection of the time-dependent transcription of genes coding enzymes that are involved in NAD(P)+ biosynthesis reveal an unusual pattern. Transcriptional profiles of at least three transcripts show two peaks, namely those of nicotinamidase, of nicotinate-nucleotide adenylyltransferase and of NAD(P)+ transhydrogenase, as compared to most other transcripts in the parasite transcriptome that are monophasic. The reason for this pattern is unclear as biochemical data are uanavilable for any physiological intepretation, but it may suggest that the the enzymes are not stable. Assuming that the first smaller peak of nicotinate-nucleotide adenylyltransferase (20 HPI) is sufficient for adequate expression of enzymatic activity, the biosynthesis of NAD(P)+ should peak when NAD+ synthetase is at its peak, i.e., at 28 HPI. Thus, by 28 HPI the transcripts of all enzymes necessary for NAD+ synthesis are fully deployed and somewhat later, synthesis itself is probably fully deployed. This time pattern means that important activities, such as glycolysis (the transcription of genes coding for glycolytic enzymes starts to peak at 9 HPI and starts to decrease at 24 HPI  At earlier stages glycolysis and PPP activity probably depend on the pool of NAD(P)+ that were present in the invading merozoite. For the full activation of glycolysis at the trophozoite stage , the pool of NAD(P)+ has to be significantly amplified. As can be seen in Table 3, several genes coding for enzymes requiring NAD(H) are transcribed earlier than the complete transcription of genes related to NAD+ synthesis. Such an outstanding exception is that of inosine-5'-monophosphate dehydrogenase, an essential enzyme in the purine metabolic pathway: it is transcribed too early to allow its translated product to be functionally useful. The functional meaning of the second peaks of nicotinamidase and of nicotinate-nucleotide adenylyltransferase is enigmatic since the transcription of all other enzyme-coding genes declines to a minimum when they peak. For being meaningful physiologically, the stability of all other enzymes must be sustained with time. Indeed, it has been recently shown that the levels of some proteins such as methionine adenosyltransferase, ornithine aminotransferase, lactate dehydrogenase, glyceraldehyde 3-phosphate dehydrogenase and enolase, are not only increased following transcription, but further increase after their transcript levels decline . Finally, NAD+ kinase is essential for the production of NADP+. Its absence from the genome is indeed very perplexing because biochemical evidence indicate that the parasite is able to synthesize NADP+  and the presence of many enzymes that need it as a cofactor, implicate that its synthesis is essential for parasite growth. As long as the gene (or some surrogate mecahnism) is not identified, nothing can be said about the coordination of NADP+ biosynthesis and the expression of enzymes that utilize it (Table 1).
Transhydrogenase operates at an important interface between NAD(H) and NADP(H) and between the mitochondrial proton electrochemical gradient ??; . Under regular physiological conditions, the enzyme is a consumer of ??:
NADH + NADP+ + H+out_ NAD+ + NADPH + H+in.
The energy of the gradient can drive the [NADPH][NAD+]/[NADP+][NADH] ratio to values >400. Transhydrogenation can also function in the reverse direction from NADPH to NAD+. This is accompanied by outward proton translocation and formation of ??. In this mode, the enzyme utilizes substrate binding energy for proton pumping. Therefore, in terms of energy transduction, the transhydrogenase works in principle like the ATP synthase complex of mitochondria, the proton ATPase. Given the fact that the parasite genome does not have the full complement of genes coding for the mitochondrial proton ATPase , it is tempting to suggest that the transhydrogenase could fulfill such role. The transcription of the gene coding for transhydrogenase shows two very distinct peaks at 20 and 30 HPI, with no detectable transcription between them. It may well be that the second peak is adjusted to the time of elongation and division of the single mitochondrion .
Thiamine diphosphate utilizing enzymes. Enzymes are arranged by their sequential functional order. They are given by their name, their EC numbers, the gene identification (PfID) in the Plasmodium genome database (PlasmoDB), the time (in hours post invasion (HPI)) in the parasite's developmental cycle when they are maximally transcribed obtained from the IDC database, the metabolic function of the enzyme.
Pyruvate dehydrogenase E1
Apicoplast fatty acid synthesis
Pentose phosphate pathway
Glyoxylate and dicarboxylate metabolism
Leucine, isoleucine and valine degradation
Mitochondrial TCA cycle
The transcription of all genes coding for enzymes involved in thiamine pyrophosphate seems to be coordinated, single phased and peaking between 20 and 30 HPI. If thiamine is obtained from the host and thiamine pyrophosphate is synthesized by the single step mediated by thiamine diphosphokinase, the peak transcription of this gene at 28 HPI lags by several hours after that of transketolase (17 HPI), but since transketoalse is not the expression time-setter of PPP, this lag does not seem to limit the full activity of PPP. However, if most of the thiamine is generated endogenously by the parasite, the supply of this precursor will peak only at 33 HPI, thus limiting full PPP activity. It is not unlikely that both processes occur in tandem or that at advanced stage of parasite development, the need for thiamine cannot be met anymore by exogenous supply and the endogenous synthesis joins the game.
The analysis of time-dependence transcription of parasite genes concluded that the parasite has evolved a highly specialized mode of transcriptional regulation that produces a continuous cascade of gene expression, beginning with genes corresponding to general cellular processes, such as protein synthesis, and ending with Plasmodium-specific functionalities, such as genes involved in erythrocyte invasion . However, a meticulous analysis shows marked and important deviations from this prototype that reveal a lack of coordinated transcription of genes coding for enzymes of the same metabolic pathway and between pathways. There are three most straightforward explanations for these apparent discrepancies. First, there are additional enzymes facilitating the "missing" activities and their identity was not revealed by the present annotations due to their diverse amino acid sequence. Second, the misaligned transcriptional regulation reflect an intricate interplay of the biosynthetic pathways where delayed production of metabolites in one pathway functions as a rate limiting factor for other pathway, which is otherwise fully deployed. Last but not least, post-transcriptional regulation may also play a role. All theories create an intriguing possibility for further studies. Clearly this effort will be enhanced by substantial progress in proteomics and most importantly, direct biochemical demonstrations of activities of individual enzymes and entire pathways.
We thank Professor I. Ohad for critical reading of the manuscript.
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